-
Physiological Reviews Jul 2021A diverse array of sex determination () mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed... (Review)
Review
A diverse array of sex determination () mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed mechanisms (mammals) to functional sex change in fishes (sequential hermaphroditic fishes). A major landmark in vertebrate was the discovery of the gene in 1990. Since that time, many attempts to clone an ortholog from nonmammalian vertebrates remained unsuccessful, until 2002, when was discovered as the gene of a small fish, medaka. Surprisingly, however, was found in only 2 species among more than 20 species of medaka, suggesting a large diversity of genes among vertebrates. Considerable progress has been made over the last 3 decades, such that it is now possible to formulate reasonable paradigms of how and gonadal sex differentiation may work in some model vertebrate species. This review outlines our current understanding of vertebrate and gonadal sex differentiation, with a focus on the molecular and cellular mechanisms involved. An impressive number of genes and factors have been discovered that play important roles in testicular and ovarian differentiation. An antagonism between the male and female pathway genes exists in gonads during both sex differentiation and, surprisingly, even as adults, suggesting that, in addition to sex-changing fishes, gonochoristic vertebrates including mice maintain some degree of gonadal sexual plasticity into adulthood. Importantly, a review of various mechanisms among vertebrates suggests that this is the ideal biological event that can make us understand the evolutionary conundrums underlying speciation and species diversity.
Topics: Animals; Female; Gonads; Male; Sex Determination Processes; Sex Differentiation; Vertebrates
PubMed: 33180655
DOI: 10.1152/physrev.00044.2019 -
Frontiers in Endocrinology 2020Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex.... (Review)
Review
Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Müllerian hormone (AMH) production, which leads to the development of ambiguous or female genitalia. The process of sex differentiation can also be disrupted at the stage of genital differentiation, due to isolated defects in androgen or AMH secretion, but not both. These are forms of fetal-onset hypogonadism with dissociated gonadal dysfunction. In this review, we present a perspective on impaired testicular endocrine function, i.e., fetal-onset male hypogonadism, resulting in incomplete virilization at birth.
Topics: Disorders of Sex Development; Humans; Hypogonadism; Male
PubMed: 32351452
DOI: 10.3389/fendo.2020.00211 -
Nature Jul 2022Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries. Historically, limited tissue...
Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal-mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15 and TREM2 fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.
Topics: Animals; Cell Lineage; Chromatin; Female; Germ Cells; Granulosa Cells; Humans; Immunoglobulins; Macrophages; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Microscopy, Fluorescence; Ovary; PAX8 Transcription Factor; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Receptors, Immunologic; Sex Differentiation; Single-Cell Analysis; Testis; Transcriptome
PubMed: 35794482
DOI: 10.1038/s41586-022-04918-4 -
Journal of Clinical Medicine Nov 2020In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification... (Review)
Review
In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification of disorders or anomalies of sex development. Anomalies in sex determination without sex ambiguity include gonadal dysgenesis, polysomies, male XX, and Klinefelter syndrome (dysgenesis and polysomies with a female phenotype; and sex reversal and Klinefelter with a male phenotype). Other infertility situations could also be included here as minor degrees of dysgenesis. Anomalies in sex determination with sex ambiguity should (usually) include testicular dysgenesis and ovotesticular disorders. Among the anomalies in sex differentiation, we include: (1) males with androgen deficiency (MAD) that correspond to those individuals whose karyotype and gonads are male (XY and testes), but the phenotype can be female due to different hormonal abnormalities. (2) females with androgen excess (FAE); these patients have ovaries and a 46,XX karyotype, but present varying degrees of external genital virilization as a result of an enzyme abnormality that affects adrenal steroid biosynthesis and leads to congenital adrenal hyperplasia; less frequently, this can be caused by iatrogenia or tumors. (3) Kallman syndrome. All of these anomalies are reviewed and analyzed herein, as well as related fertility problems.
PubMed: 33158283
DOI: 10.3390/jcm9113555 -
Science (New York, N.Y.) Nov 2023Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary...
Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.
Topics: Animals; Female; Male; Mice; Ovary; Sex Determination Processes; Sex-Determining Region Y Protein; Testis; WT1 Proteins; Protein Isoforms
PubMed: 37917714
DOI: 10.1126/science.add8831 -
Endocrinology Oct 2020Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to "activation" of adult... (Review)
Review
Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to "activation" of adult circuits. Sexual behavior is an ideal system in which to investigate the mechanisms underlying hormonal activation of neural circuits. Sexual behavior is a hormonally regulated, innate social behavior found across species. Although both sexes seek out and engage in sexual behavior, the specific actions involved in mating are sexually dimorphic. Thus, the neural circuits mediating sexual motivation and behavior in males and females are overlapping yet distinct. Furthermore, sexual behavior is strongly dependent on circulating gonadal hormones in both sexes. There has been significant recent progress on elucidating how gonadal hormones modulate physiological properties within sexual behavior circuits with consequences for behavior. Therefore, in this mini-review we review the neural circuits of male and female sexual motivation and behavior, from initial sensory detection of pheromones to the extended amygdala and on to medial hypothalamic nuclei and reward systems. We also discuss how gonadal hormones impact the physiology and functioning of each node within these circuits. By better understanding the myriad of ways in which gonadal hormones impact sexual behavior circuits, we can gain a richer and more complete appreciation for the neural substrates of complex behavior.
Topics: Adult; Animals; Brain; Female; Hormones; Humans; Male; Nerve Net; Sex Characteristics; Sex Differentiation; Sexual Behavior; Sexual Behavior, Animal
PubMed: 32845294
DOI: 10.1210/endocr/bqaa150 -
Journal of Neuroendocrinology Feb 2022Widespread sex differences in human brain structure and function have been reported. Research on animal models has demonstrated that sex differences in brain and... (Review)
Review
Widespread sex differences in human brain structure and function have been reported. Research on animal models has demonstrated that sex differences in brain and behavior are induced by steroid hormones during specific, hormone sensitive, developmental periods. It was shown that typical male neural and behavioral characteristics develop under the influence of testosterone, mostly acting during perinatal development. By contrast, typical female neural and behavioral characteristics may actually develop under the influence of estradiol during a specific prepubertal period. This review provides an overview of our current knowledge on the role of steroid hormones in the sexual differentiation of the human brain. Both clinical and neuroimaging data obtained in patients with altered androgen levels/actions (i.e., congenital adrenal hyperplasia or complete androgen insensitivity syndrome [CAIS]), point to an important role of (prenatal) androgens in inducing typical male neural and psychosexual characteristics in humans. In contrast to rodents, there appears to be no obvious role for estrogens in masculinizing the human brain. Furthermore, data from CAIS also suggest a contribution of sex chromosome genes to the development of the human brain. The final part of this review is dedicated to a brief discussion of gender incongruence, also known as gender dysphoria, which has been associated with an altered or less pronounced sexual differentiation of the brain.
Topics: Androgen-Insensitivity Syndrome; Androgens; Animals; Brain; Female; Gonadal Steroid Hormones; Humans; Male; Pregnancy; Sex Differentiation; Steroids
PubMed: 34708466
DOI: 10.1111/jne.13050 -
Cellular and Molecular Life Sciences :... Dec 2021Zebrafish have emerged as a major model organism to study vertebrate reproduction due to their high fecundity and external development of eggs and embryos. The... (Review)
Review
Zebrafish have emerged as a major model organism to study vertebrate reproduction due to their high fecundity and external development of eggs and embryos. The mechanisms through which zebrafish determine their sex have come under extensive investigation, as they lack a definite sex-determining chromosome and appear to have a highly complex method of sex determination. Single-gene mutagenesis has been employed to isolate the function of genes that determine zebrafish sex and regulate sex-specific differentiation, and to explore the interactions of genes that promote female or male sexual fate. In this review, we focus on recent advances in understanding of the mechanisms, including genetic and environmental factors, governing zebrafish sex development with comparisons to gene functions in other species to highlight conserved and potentially species-specific mechanisms for specifying and maintaining sexual fate.
Topics: Animals; Female; Germ Cells; Male; Protein Processing, Post-Translational; RNA; Sex Determination Processes; Sex Differentiation; Zebrafish
PubMed: 34936027
DOI: 10.1007/s00018-021-04066-4